The mammalian hematopoietic system contains a variety of cell types which include myeloid and lymphoid cells. These cells act as effectors of immune responses and are responsible for combating infection and disease. The lymphoid cells are comprised of mature B and T lymphocytes, each cell bearing receptors specific for distinct antigens. The lymphocyte population plays an important role in mounting a humoral and cell-mediated response to foreign antigens.
All mature T lymphocytes express the CD3 cell surface molecule, but consist of two basic subtypes based on their mutually exclusive expression of cell surface molecules CD4 and CD8. CD4.sup.+ T cells are generally involved in "helper" functions in immune responses and secrete cytokine molecules, in particular IL-2, IL-4 or IL-7, upon which the cytotoxic CD8.sup.+ T cells are dependent. CD4.sup.+ are often referred to as T helper (T.sub.H) cells. CD8.sup.+ cells are involved in "effector" functions in immune responses, such as direct cytotoxic destruction of target cells bearing foreign antigens, and represent an important mechanism for resistance to viral infections and tumors. The functional distinction between CD4.sup.+ and CD8.sup.+ T cells is based on the ability of CD4.sup.+ cells to recognize antigen presented in association with class II MHC molecules, and CD8.sup.+ cells to recognize antigen presented in association with class I MHC molecules. The CD8.sup.+ cells that mediate this lyric function are designated cytotoxic T lymphocytes (CTLs). Although most CTL are of the CD8.sup.+ phenotype, some CTL of the CD4.sup.+ phenotype have been described. Generally, individual CFLs (whether CD8.sup.+ or CD4.sup.+) are antigen-specific.
CTLs are dependent on helper T (T.sub.H) cell-derived cytokines, such as IL-2, IL-4 and IL-7, for growth and proliferation in response to foreign antigens. (Zinkernagel and Doherty, Adv. Immunol. 27:51, 1979; Male et al., Advanced Immunology, Chap. 7, Gower Publ., London, 1987; Jacobson et al., J. Immunol. 133:754, 1984). IL-2, for example, is a potent mitogen for cytotoxic T lymphocytes (Gillis and Smith, Nature 268:154, 1977), and the combination of antigen and IL-2 cause proliferation of primary CD8.sup.+ T cells in vitro. The importance of IL-2 for the growth and maintenance of the CD8.sup.+ CTL in vivo has been documented in models of adoptive immunotherapy in which the therapeutic efficacy of transferred anti-retroviral CD8.sup.+ cells is enhanced on subsequent administration of IL-2 (Cheever et al., J. Exp. Med. 155:968, 1982; Reddehase et al., J. Virol. 61:3102, 1987). IL-4 and IL-7 are also capable of stimulating the proliferation of mature CD8.sup.+ CTL (Alderson et al., J. Exp. Med. 172:577, 1990).
Due to the specificity of T cells for foreign antigens, considerable research has been focused on the use of T cells in treating viral infections and malignant tumors. Cytotoxic T cells specific for a particular type of tumor antigen can be isolated and administered to a patient having the tumor, with the effect that the CTLs ameliorate the tumor. It has been demonstrated, for example, that tumor-specific T cells can not only be generated to experimental tumors in mice, but also that T cells with apparent tumor specificity can be isolated from cancer patients. Such human tumor-infiltrating lymphocytes (TILs) have been expanded in vitro and used to treat cancer patients, generating significant enthusiasm for human adoptive immunotherapy with tumor-specific T cells (Rosenberg, et al., N. Engl. J. Med. 319:1767, 1988).
Similar studies using cytotoxic T cells specific for viral antigens have also been conducted in animal models. Human HIV specific CTL of both the CD8.sup.+ (Walker et al., Nature 328:345, 1987; Plata et al., Nature 328:348, 1987) and CD4.sup.+ (Siliciano et al., Cell 54:561, 1988) phenotype have been isolated and characterized. HIV-specific CTL are classical CTL in that their proliferative and cytotoxic responses are antigen-specific and MHC-restricted (Walker et al., supra; Plata et al., supra; Chenciner et al., Eur. J. Immunol. 19:1537, 1989; Walker et al., Proc. Natl. Acad. Sci. USA 86:9514, 1989), in common with the numerous mouse and human CTL clones which have been characterized which are specific for viral, tumor or allospecific antigens.
Although many antigen-specific T cell clones have been isolated, the use of tumorspecific T cell clones generated in vitro has been shown to have definite limitations in tumor therapy. It has been demonstrated in several therapeutic models that the efficacy of cytolytic CD8.sup.+ T cells is limited by a dependency on exogenous IL-2 (produced by T.sub.H cells), a finding that has been substantiated in human adoptive therapy trials in which administration of exogenous IL-2 appears essential for optimal therapeutic efficacy (Rosenberg, et al., N. Engl. J. Med. 319:1767, 1988; Klarnet et al., in Role of Interleukin-2Activated Killer Cells in Cancer, Lotzova and Herberman (eds.), CRC Pres, Florida, Chap. 14, pp. 199-218, 1990). Thus, while in vitro T cell cloning techniques provide a means to generate large numbers of T cells with demonstrable tumor or viral specificity, the full potential of using such antigen-specific T cells in therapy appears to be limited by their dependency on T.sub.H cells.
In some limited instances the problem of T.sub.H dependency may be circumvented by using a particular class of cells known to function independent of T.sub.H cells. These cells are known as helper-independent cytolytic CD8.sup.+ T cells (HIT.sub.c) (Klarnet et al., J. Immunol. 142:2187, 1989) and have been identified in populations of primary (i.e., freshly isolated from in vivo sources) CD8.sup.+ CTL (Sprent and Schaefer, J. Exp. Med. 162:21068, 1985; Andros et al., J. Exp. Med. 159:647, 1984). HIT.sub.c cells produce sufficient IL-2 to grow independently of CD4.sup.+ cells and the cytokines they produce. HIT.sub.c cells are also known to express plasma membrane IL-1 receptors (IL-1R) and require IL-1 for their IL-2-independent proliferation (Klarnet et al., 1989, supra). This is in contrast to conventional CD8.sup.+ CTL which do not express detectable IL-1R on their surface (Lowenthal and MacDonald, 1987). HIT.sub.c cells have been generated which are specific for a range of antigens, including tumor, viral and alloantigens (von Boehmer et al., J. Immunol. 133:59, 1984; Klarnet et al., J. Immunol. 138:4012, 1987; and Andrus et al., J. Exp. Med. 159:647, 1984; Mizuochi et al., J. Immunol 142:270, 1989). HIT.sub.c specific for a retrovirally transformed tumor have been shown to eradicate the tumor cells and persist long-term in vivo following their engraftment (Klarnet et al., 1989, supra). Unfortunately, HIT.sub.c cells having specificity for many important antigens, such as HIV, have not yet been isolated.
In order to realize the full potential of antigen-specific T cells in therapy, it will be necessary to develop a more complete repertoire of T.sub.H -independent cytolytic T cells.